Communication between mother and fetus : Imprinting and endocrine adaptations to pregnancy

背景：怀孕与高发病率和死亡率相关，尽管在过去的50年里，医疗保健取得了广泛的进步。此外，随着一般人群中肥胖和糖尿病的发病率上升，妊娠结果恶化，孕产妇和胎儿健康仍然是一个重大的公共卫生问题。这背后的原因是缺乏对能量是如何在怀孕期间从母亲转移到胎儿的理解，以及由于母亲饮食改变和遗传因素之间的相互作用，能量是如何出错的。此外，很少有诊断工具可用于检测胎儿的能量供应何时受到损害，因此儿科临床医生缺乏信息，无法根据这些信息采取行动，以改善孕妇及其子女的结局。目的和目标：我们建议增加我们关于胎儿在怀孕期间如何从母亲获得资源的基本知识。在妊娠后期，胎儿生长非常迅速，母亲必须能够提供最大的资源。母亲的身体知道这样做的一种方式是，胎盘向母体循环中释放激素，这标志着从食物中获得的母体营养物质的再分配。例如，在妊娠后期，母亲不太可能将过量的膳食葡萄糖转化为储存的脂肪，相反，葡萄糖通过胎盘运输，成为胎儿生长的燃料。我们研究的是一种名为DLK1的信号分子，它在老鼠怀孕期间会增加母体血液中的浓度。其他人发现，母体DLK1的增加也发生在人类怀孕期间。我们最近证明（使用Dlk1基因发生突变的转基因小鼠）这种分子一定来自胎儿或胎盘。我们打算发现DLK1是否是一种胎盘激素，以及人类胎盘是否也是DLK1的来源。在未怀孕的女性中，血液中的DLK1含量很低。我们发现，产生高水平DLK1的转基因小鼠以脂肪形式储存的能量更少，并且使用脂肪而不是葡萄糖作为能量来源。这与怀孕期间DLK1自然高的情况非常相似。我们假设胎儿使用DLK1作为信号来指示母亲为胎儿的生长提供更多的能量。我们将测试这一假设，并旨在发现这种潜在的新型激素是如何起作用的。DLK1是由一组基因中的一个成员编码的，这些基因以一种不寻常的方式受到调节。基因组中的每个基因都有两个拷贝，一个遗传自父亲，另一个遗传自母亲。在大多数情况下，这两种基因形成了产生蛋白质的模板。然而，哺乳动物基因组中大约有100个基因只从一个亲本拷贝中表达，而另一个拷贝是沉默的，即印迹基因。众所周知，印迹基因编码的分子在生长和发育以及成年期的代谢过程中具有至关重要的功能。众所周知，在怀孕期间，母体脑垂体的大小和激素分泌会发生变化。DLK1等印迹产物在脑垂体中表达，受妊娠调节。我们想了解印迹基因是否在怀孕期间介导母体垂体功能，以及它们在此期间是如何被激活的。这很重要，因为如果母亲的脑垂体不能适当地适应怀孕，母亲和胎儿的生长和健康都会受到损害。潜在的应用和好处。母体DLK1水平在正常妊娠和胎儿生长受损的妊娠（如子痫前期和宫内生长受限）之间可能存在差异。我们希望通过了解其来源和功能，我们可以在未来将母体DLK1水平作为胎儿健康的一种新的非侵入性标志物，为临床实践提供信息，以改善妊娠结局

Context:Pregnancy is associated with high rates of morbidity and mortality despite broad advances in healthcare over the last 50 years. In addition, as rates of obesity and diabetes increase in the general population, the outcomes of pregnancy have worsened and maternal and fetal health remains a significant public health issue. Underlying this is a lack understanding of how energy is diverted to the fetus from the mother during gestation, and how this goes wrong as a result of the interaction between altered maternal diet and genetic factors. In addition, there are few diagnostic tools available to detect when the energy supply to the fetus is compromised, and consequently paediatric clinicians have a paucity of information upon which to act to improve outcomes for pregnant women and their children.Aims and objectives:We propose to increase our basic knowledge about how the fetus gains resources from the mother during pregnancy. In late gestation, when the fetus is growing very rapidly, the mother must be able to deliver maximal resources. One way in which the mother's body knows to do this is because the placenta releases hormones into the maternal circulation that signal redistribution of maternal nutrients obtained from food. For example, during late gestation the mother becomes less likely to convert excess dietary glucose into stored fat, and instead the glucose is transported across the placenta to become fuel for fetal growth. We work on a signalling molecule called DLK1, which increases in concentration in maternal blood during pregnancy in mice. Others have found that this increase in maternal DLK1 also occurs during human pregnancy. We recently proved (using genetically modified mice that have a mutation in their Dlk1 gene) that this molecule must come from the fetus or the placenta. We propose to discover if DLK1 is a placental hormone, and if the human placenta is also a source of DLK1. In non-pregnant females the amount of DLK1 in the blood is low. We found that genetically modified mice that make high levels of DLK1 store less energy as fat, and use fats rather than glucose as an energy source. This is very similar to what happens in pregnancy when DLK1 is naturally high. We hypothesise is that the fetus uses DLK1 as a signal to instruct the mother to make more energy available for fetal growth. We will test this hypothesis, and aim to discover how this potentially novel hormone works.DLK1 is encoded by a member of a group of genes that are regulated in an unusual way. Each gene in the genome is present in two copies, one inherited from the father and the other from the mother. In most circumstances both of these genes form the template for producing proteins. However, a group of ~100 genes in the mammalian genome are only expressed from one parental copy, and the other copy is silenced, the imprinted genes. Imprinted genes are known to encode molecules that have crucial functions in growth and development, as well as in metabolic processes during adulthood.The maternal pituitary gland is known to change its size and hormone output during pregnancy. DLK1, and other imprinted products are expressed in the pituitary gland, and are regulated by pregnancy. We would like to understand if imprinted genes mediate maternal pituitary function during pregnancy, and how they are activated during this period. This is important because if the maternal pituitary gland does not adapt appropriately to pregnancy the growth and wellbeing of both mother and fetus are compromised.Potential applications and benefits.It is likely that maternal DLK1 levels differ between normal pregnancies and those where fetal growth is compromised such as in preeclampsia and intrauterine growth restriction. Our hope is that by understanding its source and function we could in the future use maternal DLK1 levels as a novel non-invasive marker of fetal well being, informing clinical practice to improve pregnancy outcomes